Bexarotene in Preventing Breast Cancer in Patients at High Risk for Breast Cancer

Phase 1

Completed

Conditions: Breast Ductal Carcinoma In Situ
Breast Atypical Ductal Hyperplasia
Breast Atypical Lobular Hyperplasia
Invasive Breast Carcinoma
Breast Lobular Carcinoma In Situ

Interventions: Drug: Bexarotene
Other: Questionnaire Administration

Registration Number: NCT03323658

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase I trial studies the side effects and best dose of bexarotene in preventing breast cancer in patients at high risk for breast cancer. Bexarotene belongs to a class of drugs that are called rexinoids, and it may reduce the incidence of breast tumors.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of topical bexarotene 1% (weight by weight \[w/w\]) gel for evaluation in healthy women. (Dose Escalation Group) II. Conduct an intervention of topical 1% bexarotene gel to an unaffected breast of healthy women at high risk for breast cancer for 4 weeks at the maximum tolerated dose (MTD) as determined during the dose escalation group phase to assess bexarotene concentration in the breast tissue. (Dose Expansion Group)

SECONDARY OBJECTIVES:

I. To detect bexarotene concentration in the serum at baseline and at 4 weeks of treatment.

II. To detect bexarotene concentration in the breast tissue at 4 weeks of treatment in the dose escalation group.

III. To investigate the effects of topical bexarotene on serum biomarkers, we will determine the change from baseline in i) lipid biomarkers (total cholesterol, triglycerides, low density lipoprotein \[LDL\], high density lipoprotein \[HDL\]), ii) thyroid function biomarkers (thyroid stimulating hormone \[TSH\], T4, T3), iii) calcium.

EXPLORATORY OBJECTIVE:

I. To examine changes in gene expression associated with retinoid action. (Dose Expansion Group)

OUTLINE: This is a dose-escalation study.

Group 1 will apply 10mg bexarotene topically to one breast every other day (QOD) for 4 weeks; Group 2 will apply 10mg bexarotene topically to one breast every other day (QOD) for 1 week and then daily for 3 weeks after confirmation that toxicity is at an acceptable range; Group 3 will apply 10mg bexarotene topically to one breast every other day (QOD) for 1 week, then daily for 1 week, and then 20mg daily for 2 weeks after confirmation that toxicity is at an acceptable range.

After completion of study treatment, patients are followed up at 30 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 24

Inclusion Criteria

Participants must be at high risk as defined by a history of breast cancer (invasive or ductal breast carcinoma in situ [DCIS]) and be at least 5 years out from diagnosis, or lobular carcinoma in situ (LCIS), or proliferative benign breast disease such atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) or genetic test confirmation of BRCA 1/2 mutation carrier or have a breast cancer risk assessment >= 1.7% in 5 years or a lifetime risk >= 20%
No evidence of disease (in situ or invasive cancer that would normally be treated by resection) at trial entry as determined by the investigator; diagnosis of invasive cancer must be at least 5 years prior to initiation on trial
Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
Leukocytes >= 3,000/microliter
Absolute neutrophil count >= 1,500/microliter
Platelets >= 100,000/microliter
Total bilirubin within normal institutional limits
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal (ULN)
Creatinine =< 1.5 x institutional ULN
Hemoglobin >= 10 g/dL
Thyroid-stimulating hormone (TSH) within normal institutional limits
Triglycerides =< 300 mg/dl
Total cholesterol =< 300 mg/dl
>= 6 months from all previous breast cancer treatment (including endocrine therapy)
Participants must have adequate accessible breast tissue as determined by the treating physician, consisting of one breast unaffected by invasive cancer, which has not been radiated; a history of benign core biopsy of this breast will be permitted
Participants need to have had any breast imaging with a normal/benign (bi-rads 1 or 2) result within 180 days of day 0 and no further routine breast imaging planned during the course of the study (4 weeks); exception: if the mammogram result was a bi-rads 0 and the imaging work-up (ultrasound and/or magnetic resonance imaging [MRI]) result comes back normal/benign (bi-rads 1 or 2) before treatment initiation, then participant is eligible.
For women of childbearing potential; negative pregnancy testing within 72 hours prior to or on study visit #1 (day 0) and willingness to use adequate contraception during the study intervention; OR post-menopausal defined as any one of the following 1) prior hysterectomy, 2) absence of menstrual period for 1 year in the absence of prior chemotherapy or 3) absence of menstrual period for 2 years in women with a prior history of chemotherapy exposure who were pre-menopausal prior to chemotherapy; in women of childbearing potential, effective contraception must be used for one month prior to the initiation of therapy, during therapy, and for at least one month following discontinuation of therapy; it is recommended that two reliable forms of contraception be used simultaneously; if participants are interested in enrolling and have not met the requirement for contraception, they will be seen in the clinic in 1 month for re-evaluation once they have met this requirement and ensure all other eligibility criteria is met prior to dose assignment
Willingness to comply with all study interventions and follow-up procedures including the ability to apply the study drug to the breast
Ability to understand and the willingness to sign a written informed consent document
Ability to avoid exposure of the treated breast area to sunlight and artificial ultraviolet light during the use of bexarotene gel

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to bexarotene gel, oral or topical retinoids
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, thromboembolic disease, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant, or had given birth, or nursed at any time during the last 12 months
Women with a history of any cancer within the last 3 years, except for non-melanoma skin cancer; history of breast cancer must be at least > 5 years from diagnosis
Prior bilateral breast surgery (mastectomy, segmental mastectomy, or breast augmentation surgery including breast implants or breast reductions) or combination of breast radiation and surgery involving both breasts
Prior history or evidence of metastatic breast cancer
Prior history of histologically confirmed bilateral invasive breast cancer
Current use or < 6 months since use of selective estrogen receptor modulator (SERMS) or aromatase inhibitors or any other investigational treatment for breast cancer prevention or therapy
Skin lesions that disrupt the stratum corneum (e.g., eczema, ulceration) or any breakdown of the skin
Current use of a retinol containing agent or any retinoid analogue drug within the last 30 days
Dietary vitamin A intake >= 5,000 IU/day (as determined by dietary supplementation)
Treatment with any investigational drug or investigational biologic within 30 days of initiating study treatment or during the study
History of human immunodeficiency virus (HIV) or active hepatitis C

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Prevention (bexarotene)	Questionnaire Administration	Group 1 will apply 10mg bexarotene topically to one breast QOD for 4 weeks; Group 2 will apply 10mg bexarotene topically to one breast QOD for 1 week and then daily for 3 weeks after confirmation that toxicity is at an acceptable range; Group 3 will apply 10mg bexarotene topically to one breast QOD for 1 week, then daily for 1 week, and then 20mg daily for 2 weeks after confirmation that toxicity is at an acceptable range.
Prevention (bexarotene)	Bexarotene	Group 1 will apply 10mg bexarotene topically to one breast QOD for 4 weeks; Group 2 will apply 10mg bexarotene topically to one breast QOD for 1 week and then daily for 3 weeks after confirmation that toxicity is at an acceptable range; Group 3 will apply 10mg bexarotene topically to one breast QOD for 1 week, then daily for 1 week, and then 20mg daily for 2 weeks after confirmation that toxicity is at an acceptable range.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities)	4 weeks of treatment, Up to 30 days after completion of study drug for AE assessments	Dose Limiting Toxicity (DLT) is defined as a grade 2 skin adverse event that persists for at least 6 days or any grade 3 or greater adverse event possibly, probably, or definitely related to the study drug. In addition, a DLT will be a grade 2 skin adverse event that recurs and persists for at least 3 days.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Bexarotene Concentration in Tissue	end of treatment, up to 4 weeks	Breast tissue concentrations were available only in those women who underwent breast biopsies. Tissue samples: Not detected (below the quantitation limit of 2.5 ng/g for a 10mg sample) and Trace levels detected (below the LOQ of 2.5ng/g; estimated value).
Number of Participants With Changes in Markers of Systemic Toxicity	Baseline up to 28 days	Serum biomarkers to be tested will be total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, thyroid-stimulating hormone, T4, T3, and calcium. Will be summarized using mean, standard deviation and median (range) for continuous variables at each time point. Wilcoxon rank-sum test may be used to examine the difference of continuous variables between participants' characteristics groups. Will be plotted as functions of time (baseline, week 1, week 2, and week 4). Linear mixed effect model will be applied to model the biomarker change over time for all participants. Appropriate transformation and regression model will be used to ensure the model fit.
Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected	baseline and end of treatment, up to 4 weeks	Plasma concentrations of bexarotene were evaluated in all participants at baseline and at end of study. Plasma samples: ND = Not detected (below the quantitation limit of 0.5 ng/mL) TDL = Trace levels detected (below the LOQ of 0.5ng/mL; estimated value)